Bacteriophage (or “phage”) are viruses that infect bacterial cells. Bacteriophage were first identified in the early 20th century and their property of being able infect and destroy bacterial cells was widely employed in a therapeutic context for the treatment of bacterial infections with significant effect. However, the lack of well controlled studies regarding the application of phage therapy in the 1930s and 1940s led significant to issues regarding proper dosage and treatment regimens. The reported utility of phage therapy varied widely in the literature. The lack of controlled studies for the use of phage therapy combined with the advent of small molecule antibiotics in the 1940s led to a decline in the reliance on phage therapy for the treatment of bacterial infections. Continuing improvements in small molecule antibiotic compounds led to their near universal adoption in the clinic as the standard of care for the treatment of bacterial infections. As a result, the necessary well controlled clinical studies to standardize phage therapy were not conducted and phage therapy widely fell into disrepute. However, the growing acceptance of biological therapies such as engineered viruses and modified cellular therapies has resulted in many investigators revisiting the use of phage in the treatment of bacterial infections, particularly those that are resistant to small molecule therapies such as MRSA and a reassessment of their safety. Several clinical investigations have been initiated to evaluate the use of bacteriophage in the clinic. For example, the PHAGOBURN study (ClinicalTrials.gov Identifier: NCT02116010), a EU Framework 7 funded program is investigating the use of cocktails of E. coli phages and Pseudomonas aeruginosa in the treatment of burn victims Since 2006, the United States Food and Drug Administration has approved the use of bacteriophages for the selective elimination of bacteria in foods such as Listeria monocytogenes (Listex, Micreos Food Safety BV, Wageningen, The Netherlands) and a variety of Salmonella species (SalmoFresh, IntraLytix, Inc., Baltimore, Md.), the latter being approved in 2013 as a GRAS food additive.
One hurdle to the use of bacteriophage for the treatment of systemic infections in mammals is that the phage particle is immunogenic resulting in neutralization by the mammalian immune system, particularly upon repeat administration. The immune response to systemic administration of phage results in significant variation in efficacy, circulating half-life of the phage agent and significantly limits the possibility of repeated administration of phage therapies. The administration of immunosuppressant compounds to a subject suffering from an infectious disease to avoid clearance of the bacteriophage is not clinically acceptable. Consequently, efforts have been made to mask the immunogenic character of the phage particle.
The conjugation of polyethylene glycol polymers (“PEGylation”) to biological agents to avoid immune clearance and prolong circulating half-life is well known in the art. A variety of PEGylated biological agents have been approved by regulatory authorities and are routinely used by clinicians for the treatment of a variety of diseases. Based on this experience, the PEGylation of bacteriophage has been proposed for the systemic treatment of bacterial infections. See e.g., Carlton, et al. U.S. Pat. No. 7,332,307 B2 issued Feb. 19, 2008. However, the prolonging the half-life of the phage and shielding it from immune surveillance does not provide durable protection from future infection by bacteria. In particular, some particularly lethal strains of S. aureus (typically referred to as methicillin resistant or multidrug resistant Staphylococcus aureus or MRSA) have demonstrated complex systems to avoid immune surveillance as well as the ability to rapidly adapt resistance to therapeutic agents. MRSA arose primarily through the widespread use of broad spectrum antibiotics. Consequently, the design of an agent that attacks and kills a particular strain of MRSA will likely have limited future effect as the bacteria has evolved the ability to rapidly mutate to avoid such agents.
Consequently, there is a need in the art for an antibacterial agent that enables both systemic administration and the ability to recruit and train the immune system to recognize and attack dispersed and/or recurrent infections. The present invention addresses this need.